POS0349 ABSENCE OF ASSOCIATION OF COMPLEMENT C4 GENETIC DIVERSITY WITH SERUM COMPLEMENTS, AUTOANTIBODIES AND DISEASE ACTIVITY IN SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: C. Mariaselvam, G. Seth, C. Kavadichanda, M. Thabah, K. Rajagopal, R. Tamouza, V. Negi
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Systemic Lupus Erythematosus (SLE) is characterized by low levels of serum C3 and C4. Low complements in SLE may either be due to increased consumption or decreased synthesis, the exact mechanisms of which is unknown. <i>C4</i> gene has copy number variations and exists as two functionally distinct but genetically homologous isoforms, <i>C4A</i> (0-8 copies) and <i>C4B</i> (0-3 copies). The genes are either long (L) or short (S) based on a 6.4kb Human Endogenous Retrovirus K (<i>HERV-K</i>) insertion. Low copy numbers of complement C4 genes in systemic autoimmune disorders and its link with autoantibodies, disease subgroups have been reported. <h3>Objectives</h3> To characterize <i>C4</i> and <i>C4-HERV</i> genetic diversity in SLE and its relationship with serum complement levels, autoantibodies, disease activity, clinical subgroups and HLA. <h3>Methods</h3> Genomic DNA from 70 SLE and 90 controls were used to characterize the copy numbers of <i>C4A</i> and <i>C4B</i> genes and the frequency of HERV insertion (<i>C4AL, C4BL</i>) using droplet digital polymerase chain reaction. High resolution typing of 8 HLA genes was done using next generation sequencing. Chi-square test was used to compare the frequencies of <i>C4</i>, <i>C4-HERV</i> structural elements and HLA between groups. Correlation with complement levels, number of autoantibodies present, SLEDAI and clinical subgroups was done using Spearman's nonparametric test. <h3>Results</h3> In this cohort, total <i>C4</i> gene copies ranged from 2-6 with two copies of <i>C4A</i> and <i>C4B</i> genes being frequent; there were no C4 null alleles, and a negative correlation was noted between C4A and C4B copy numbers (r=-0.3713; p&lt;0.001; Figure 1). Compared to controls, presence of two or less copies of <i>C4A</i> gene was associated with SLE risk while C4B frequency was comparable between the groups. Significantly increased frequency of <i>HERV</i> insertion in C4A than in C4B gene was observed. Of the 34 different <i>C4-HERV</i> genotypes observed, 7 were at a frequency greater than 5%. Though the frequency of <i>AL-AL-BL-BS</i> genotype was overrepresented in SLE, the difference was not statistically significant. The <i>AL-AL-AL-BS</i> genotype was significantly higher in controls than SLE (9% vs 1%, p=0.04; Table 1). HLA-DPA1*02 and DPB1*13 were more frequent in subjects with C4B &gt;2 copies than in those with C4B ≤2 copies (33% vs 61%; Pc=0.04 &amp; 5% vs 28%; Pc=0.04). There was no correlation between the <i>C4</i> as well as <i>C4-HERV</i> gene copy numbers and serum levels of complement, autoantibodies, SLEDAI and SLE clinical subgroups (Figure 1) <h3>Conclusion</h3> Our data show that, although the <i>C4A</i> and <i>C4B</i> gene diversity is different between cases and controls, it does not correlate with serum complement levels, autoantibodies, disease activity and clinical subgroups in SLE. Low <i>C4A</i> copy number and increased insertion of HERV in <i>C4A</i> may be a risk for SLE. Our findings in this small cohort need further validation in a larger homogenous SLE cohort. <h3>Acknowledgements</h3> This study was funded by "Centre Franco-Indien pour la Promotion de la Recherche Avancée (5103-1-Tamouza/Negi)" and CMM was a post-doctoral fellow of CEFIPRA 5103-1 <h3>Disclosure of Interests</h3> None Declared.